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Biomedical subjects

R Shapiro

Publications and source records attributed to R Shapiro.

At least 217 records · Page 12Linked to original sources
PubMed1995

The superiority of tacrolimus in renal transplant recipients -- the Pittsburgh experience.

Tacrolimus is a superior immunosuppressive agent in patients undergoing renal transplantation. In adults, the 1- and 3-year actuarial patient survivals were 95% and 92%, and the 1- and 3-year actuarial graft survivals were 89% and 80%. For first cadaver kidneys, the 1- and 3-year actuarial graft survivals were 91% and 82%, with a projected half-life of 11.9 years. Sixty-nine percent of successfully transplanted patients were weaned off steroids. In pediatric patients, the 1- and 4-year actuarial patient survivals were 100% and 96%, and the 1- and 4-year actuarial graft survivals were 99% and 85%. Seventy-three percent of successfully transplanted children were weaned off steroids. Tacrolimus was also useful as a rescue agent, with an initial success rate of 74%. Tacrolimus has been used successfully in kidney/ pancreas transplantation, with 100% patient, 95% kidney, and 79% pancreas graft survival. Tacrolimus should be considered the immunosuppressive agent of choice in renal transplantation.

Adolescent↗
PubMed1994

Crystal structure of human angiogenin reveals the structural basis for its functional divergence from ribonuclease.

Angiogenin, a potent inducer of neovascularization, is the only angiogenic molecule known to exhibit ribonucleolytic activity. Its overall structure, as determined at 2.4 A, is similar to that of pancreatic ribonuclease A, but it differs markedly in several distinct areas, particularly the ribonucleolytic active center and the putative receptor binding site, both of which are critically involved in biological function. Most strikingly, the site that is spatially analogous to that for pyrimidine binding in ribonuclease A differs significantly in conformation and is "obstructed" by glutamine-117. Movement of this and adjacent residues may be required for substrate binding to angiogenin and, hence, constitute a key part of its mechanism of action.

Amino Acid Sequence↗
PubMed1994

Role of glutamine-117 in the ribonucleolytic activity of human angiogenin.

The crystal structure of human angiogenin (reported in the preceding paper in this issue) reveals that the site that corresponds to the pyrimidine binding site of RNase A is obstructed by Gln-117. Mutation of this residue to Ala and Gly is here found to increase activity 11- to 18-fold and 21- to 30-fold, respectively, toward dinucleotide, polynucleotide, and cyclic nucleotide substrates, but without changing specificity. The enhanced activity of Q117G toward CpA is due to a 5-fold decrease in Km and a 6-fold increase in kcat. Its Ki value for 2'-CMP is 5-fold lower than that of native angiogenin, whereas its Ki value for 5'-AMP is unchanged. It has been reported previously that mutating Asp-116 to Ala increases activity 15-fold. The double mutant D116A/Q117A is shown to be only slightly more active than each individual mutant. The present results demonstrate that Gln-117 impedes the ribonucleolytic activity of angiogenin, as predicted by x-ray crystallography. Moreover, they suggest that prior to or during catalysis angiogenin must undergo a conformational change to reorient the C-terminal segment that contains this residue, and that a similar reorganization is required for the mutants as well. This view is supported by molecular modeling of an angiogenin-uridine vanadate complex. These in vitro findings have implications for the angiogenic activity of angiogenin in vivo.

Base Sequence↗
PubMed1994

FK506 "rescue" for resistant rejection of renal allografts under primary cyclosporine immunosuppression.

Seventy-seven patients with ongoing acute rejection on initial CsA therapy were converted to FK506 to attempt graft salvage. Fifty-nine patients had undergone primary transplantation and 18 had been retransplanted; there were 52 cadaveric and 25 living-donor transplants. The indications for conversion to FK506 were ongoing, biopsy-confirmed rejection in all patients, including vascular rejection in 20. The median interval to rescue was 2 months (range 2 weeks to 36 months) after transplantation. Sixty-one of the 77 patients (79%) had already received one or more courses of an antilymphocyte preparation (OKT3: n = 33; ALG or ATG: n = 1; OKT3+ALG/ATG: n = 27). Of the 77 patients, 57 (74%) have been successfully rescued and still have functioning grafts with a mean follow-up of 14 months, with a mean serum creatinine of 2.35 +/- 0.97 mg/dl. Eighteen patients were already dialysis-dependent at the time of conversion to FK506; of these, 9 (50%) were successfully salvaged and have a mean serum creatinine of 2.3 mg/dl. Of the 61 patients previously treated with antilymphocyte preparations, 48 (79%) were rescued. In those salvaged, prednisone doses have been lowered from 22.2 +/- 7.2 mg/day preconversion to 7.5 +/- 5.6 mg/day postconversion, and 12 patients are on FK506 monotherapy. In nondiabetics, mean serum glucose was 101.4 +/- 20.5 mg/dl preconversion and 93.2 +/- 22 postconversion (P = 0.07), uric acid 7.3 +/- 2.3 and 7.1 +/- 1.5 mg/dl (P = 0.53), and triglycerides 199.2 +/- 101.6 and 167.2 +/- 106.4 mg/dl (P = 0.06). Cholesterol levels were significantly lower following FK conversion (207.7 +/- 46.5 mg/dl pre. vs. 188.3 +/- 39.7 post., P = 0.007). FK506 is capable of salvaging renal allografts with ongoing acute rejection on CsA therapy, even when antilymphocyte preparations have been ineffective.

Adolescent↗
PubMed1994

A cell-surface proteoglycan mediates human adenocarcinoma HT-29 cell adhesion to human angiogenin.

Human angiogenin is an excellent substrate for the adhesion of HT-29 human colon adenocarcinoma cells. These cells adhere more quickly to human angiogenin than to fibronectin, laminin, collagen I, and collagen IV. Anti-angiogenin antibodies and the angiogenesis inhibitors platelet factor-4 and placental ribonuclease inhibitor prevent adhesion of HT-29 cells to angiogenin. Calcium and magnesium ions are not required for adhesion and Arg-Gly-Asp-Ser has no effect, indicating that the interaction is integrin-independent. Instead, adhesion seems to involve a heparan/chondroitin sulfate proteoglycan. Treatment of the cells with heparinase or heparitinase decreases HT-29 cell adhesion onto angiogenin but not onto collagen I. Moreover, cell adhesion is decreased by the presence of heparin or chondroitin sulfates and by preincubation of the cells with inhibitors of proteoglycan synthesis or secretion. In addition, angiogenin binds tightly to heparin-Sepharose, requiring 0.78 M NaCl for elution. Angiogenin-affinity chromatography of a 35S-, 3H-labeled HT-29 cell fraction enriched in cell-surface proteoglycans yields a single, heparinase-sensitive component of apparent molecular mass > 200 kDa, as detected by autoradiography after SDS-polyacrylamide gel electrophoresis. These results suggest that angiogenin could be an effective substrate for tumor cell adhesion during metastasis and may provide a basis for the design of inhibitors of this process.

Adenocarcinoma↗
PubMed1994

Electromyographic activity of selected trunk and hip muscles during a squat lift. Effect of varying the lumbar posture.

Electromyographic (EMG) activity of selected hip and trunk muscles was recorded during a squat lift, and the effects of two different lumbar spine postures were examined. Seven muscles were analyzed: rectus abdominis (RA), abdominal obliques (AO), erector spinae (ES), latissimus dorsi (LD), gluteus maximus (GM), biceps femoris (BF), and semitendinosus (ST). The muscles were chosen for their attachments to the thoracolumbar fascia and their potential to act on the trunk, pelvis, and hips. Seventeen healthy male subjects participated in the study. Each subject did three squat lifts with a 157-N crate, with the spine in both a lordotic and kyphotic posture. The lift was divided into four equal periods. EMG activity of each muscle was quantified for each period and normalized to the peak amplitude of a maximal voluntary isometric contraction (MVIC). A two-way analysis of variance (ANOVA) for repeated measures was used to analyze the effects of posture on the amplitude and timing of EMG activity during the lift. Two patterns of EMG activity were seen: a trunk muscle pattern (RA, AO, ES, and LD) and a hip extensor pattern (GM, BF, ST). In the trunk muscle pattern (TP), EMG activity was greatest in the first quarter and decreased as the lift progressed. In the hip extensor pattern (HP), EMG activity was least in the first quarter, increased in the second and third quarters, and decreased in the final phase of the lift. Differences (P < .05) were seen among subjects and in the timing of the muscle activity in all muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Comparison of FK-506 and cyclosporine regimens in pediatric renal transplantation.

Clinical aspects of FK-506 or cyclosporine immunosuppression regimens were evaluated in 48 consecutive pediatric renal transplant recipients. Tapering and discontinuation of prednisone was employed only in children receiving FK-506 who experienced minor or no rejection episodes during the 1st posttransplant month. At 1 year follow-up, 17 of 22 (77%) of all children with functioning allografts were receiving no prednisone (n = 13) or a mean dosage of 0.07 mg/kg per day (n = 4). During the 1st month, acute cellular rejection was more common in the FK-506 group (0.58 vs. 0.21 rejections per patient, P < 0.05) but allograft survival (92%) and renal function at 1 year posttransplant were identical in both groups. Compared with the cyclosporine regimen, FK-506 immunosuppression may be associated with a higher incidence of cytomegalovirus or reversible Epstein-Barr virus-induced lymphoproliferative disease. However, the FK-506 group had less hirsutism and gingival hypertrophy and required fewer antihypertensive medications independent of steroid use. Height standard deviation scores and weight-for-height index improved only in pre-adolescents receiving FK-506 but no prednisone (P < 0.02 and P < 0.05, respectively), but did not differ between children on FK-506 plus prednisone and those in the cyclosporine group. We conclude that the major advantages of FK-506 over cyclosporine immunosuppression are a reduced severity of hypertension and an improved cosmetic appearance which may improve long-term medical compliance. When used as monotherapy, FK-506 also shows promise in relieving the growth retardation associated with cyclosporine regimens that include prednisone.

Adolescent↗
PubMed1994

A comparison of the predicted and X-ray structures of angiogenin. Implications for further studies of model building of homologous proteins.

The three-dimensional structure of human angiogenin has been determined by X-ray crystallography and is compared here with an earlier model which predicted its structure, based on the homology of angiogenin with bovine pancreatic ribonuclease A. Comparison of the predicted model and crystal structure shows that the active-site histidine residues and the core of the angiogenin molecule, including most of the beta-strands and alpha-helices, were predicted reasonably well. However, the structure of the surface loop regions and residues near the truncated C-terminus differs significantly. The C-terminal segment includes the active-site residues Asp-116, Gln-117, and Ser-118; Gln-117 in particular has been shown to be important in affecting the ribonucleolytic activity of angiogenin. Also, the orientation of one helix in the model differed from the orientation observed experimentally by about 20 degrees, resulting in a large displacement of this chain segment. The difficulty encountered in predicting the surface loop regions has led to a new algorithm [Palmer and Scheraga (1991), J. Comput. Chem., 12, 505-526; (1992), J. Comput. Chem., 13, 329-350] for predicting the conformations of surface loops.

Amino Acid Sequence↗
PubMed1994

Extraosseous extension of Gaucher cell deposits mimicking malignancy.

Two cases are described in which patients with type I Gaucher disease developed extraosseous soft tissue masses consisting of Gaucher cell deposits. In one instance the mass destroyed the posterior cortex of the left distal femur and protruded into the soft tissues. In the second case the lesion involved the proximal tibia and gradually extended into the soft tissues. While the incidence of neoplastic disorder such as lymphoproliferative disease appears to be more common in Gaucher disease patients than in the general population, lesions of benign etiology that mimic these aggressive processes should be considered in the differential diagnosis when cortical destruction with coexisting soft tissue most is found in these patients.

Adult↗
PubMed1994

Combined liver-kidney transplantation and the effect of preformed lymphocytotoxic antibodies.

Thirty-eight sequentially placed liver and kidney allografts were evaluated with respect to patient and graft survival, and the influence of preformed lymphocytotoxic antibodies was analysed. The results suggest that the survival rate of combined liver and kidney transplantation is similar to the survival rate of liver transplantation alone. Sequentially placed kidney allografts may be protected from hyperacute rejection in the presence of donor specific lymphocytotoxic antibodies, but not in all instances. Both patient and kidney allograft survival was lower in positive crossmatch patients (33% and 17% respectively) than in negative crossmatch patients (78% and 75%). High levels of panel reactive antibodies (> 10%) also appeared to have a deleterious effect on survival, although the majority of the patients who failed also had a positive crossmatch. Although performed lymphocytotoxic antibodies are not an absolute contraindication to combined liver-kidney transplantation, they do appear to have a deleterious effect on long-term graft survival. However, more correlation with clinical parameters is needed.

Adolescent↗
PubMed1994

Chimerism after whole organ transplantation: its relationship to graft rejection and tolerance induction.

Bone marrow-derived "passenger" leukocytes that normally reside in the interstitial tissues of whole organs migrate into the recipient after transplantation and establish microchimerism. An equally important phenomenon is the reciprocal migration of circulating recipient leukocytes, which repopulate the interstitium of whole organ allografts. This bidirectional exchange and interaction of bone marrow-derived cells after organ transplantation is considered a seminal event in the acceptance of allografts and in the induction of donor-specific tolerance. The apparent dichotomous role of donor cell chimerism in the processes of organ rejection and acceptance is discussed.

Bone Marrow Cells↗
PubMed1994

Relationship of fatigued run and rapid stop to ground reaction forces, lower extremity kinematics, and muscle activation.

Fatigue may be related to lower extremity injury. The effect of lower extremity fatigue on ground reaction force production, lower extremity kinematics, and muscle activation during the landing phase of a run and rapid stop was investigated. Subjects were 19 female, Division 1 collegiate basketball and volleyball players (mean age = 20.8 +/- 1.8 years, mean weight = 71.7 +/- 6.9 kg, mean height = 174 +/- 5 cm). Dominant leg ground reaction and muscle activation data were sampled at 2,000 Hz. Lower extremity kinematic data were sampled at 200 Hz, and three-dimensional analysis was performed. Knee extensor/flexor muscle activation tended to be delayed during fatigue (p < or = .08). Maximum knee flexion tended to occur earlier during fatigue (p < or = .09). Step-wise multiple regression suggested that the knee may be the primary site of force attenuation following fatigue. During fatigue, biodynamical compensations in the mechanical properties of the knee extensor musculature, as evidenced by differences in knee kinematics and muscle activation times, may occur to enhance knee stability.

Adult↗